FOXN1,A Novel Tumor Suppressor Gene In Gastric And Colorectal Cancer

Gastric and colorectal cancers are among the most common cancers worldwide. According to the WHO statistics, they are the top fifth leading cause of cancer morbidity and mortality, this tendency will be continuing in the next few years. Tumorigenesis and development is a complex biology process which characterised by the multiple genes participation, multi-stage and multiple steps, of which the genetic changes, such as the activation of oncogene and silence of tumor suppressor gene have been regarded as the important mechanism of the tumor development.Purpose:We studied the inactivation of a novel candidate gene FOXN1, and explored its functions in the pathogenesis of gastroenterology cancers.Methods:FOXN1 expression was determined by quantitative RT-PCR and immunohistochemistry. The influences of FOXN1 on the growth, migration, apoptosis and autophagy of tumor cells were tested in vitro and in vivo. The regulation mechanism of FOXN1 was verified by Western Blot and QPCR.Results:FOXN1 expression was high in normal gastric and colonic mucosa, but silenced or reduced in most gastrointestinal tumor samples and cell lines. FOXN1 protein expression was significantly correlated with low tumor stage (P=0.003), less lymph node metastasis (P=0.003), less distant metastases (P=0.014) and longer overall survival (P=0.011) in colorectal cancer. While in gastric cancer, it was correlated with low grade infiltrating (P=0.01), low tumor stage (P=0.042) and longer overall survival (P=0.044). Restoring FOXN1 expression by transfection can inhibit tumor cell growth in vitro and in vivo, suppress tumor migration, promote apoptosis, and modulate autophagy. Besides, by using the Western Blot and Flow Cytometry, we found that FOXN1 regulates autophagy through PBBC/AKT/mTOR pathway and it can work together with apoptosis to promote tumor cell necrosis. Furthermore, the initial outcomes hint that FOXN1 may be the target gene of hsa-miR-192-5p, but this result needs further verification.Conclusions:FOXN1 was absent in most gastrointestinal tumor samples and cell lines, while restoring its expression can strongly reduce colony formation, migration, induce apoptosis and modulate autophagy in tumor cells through PI3K pathway, which suggest that FOXN1 acts as a tumor suppressor gene and it can serve as a biomarker for tumor diagnosis and risk assessment.